Transcriptional and non-transcriptional functions of IRF3 in ALD

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ABSTRACT Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2) is a highly contagious and fast-spreading infectious disease, which reached pandemic status in only four months and is spreading worldwide with millions of people being affected. The clinical spectrum of COVID-19 ranges from mild to critically ill diseases. COVID-19 can progress rapidly into acute respiratory distress syndrome (ARDS), multiorgan failure, and even death. In the midst of the COVID-19 epidemic, there is some evidence for increased alcohol purchases. Since people generally buy more alcohol during epidemics, increased alcohol consumption may result in reduced resistance to infections like COVID-19 and promote the progression of the disease. SARS-COV-2 is a positive-sense single stranded RNA (ssRNA). While alcohol consumption has not yet been shown to directly increase risk for SARS-COV-2 transmission or COVID-19 severity, alcohol negatively affects the both the innate and adaptive immune systems and increases risk for many infectious diseases. Importantly, recent data from both murine models of ethanol exposure and peripheral blood mononuclear cells (PBMCs) from patients with alcohol-associated hepatitis (AH) indicate that signaling by viral ss/dsRNA is disrupted by alcohol, analogous to impact of alcohol on signaling via bacterial products, such as LPS. The parent RO-1 (Transcriptional and non-transcriptional roles of IRF3 in ALD) for this URGENT COMPETITIVE RENEWAL, we are investigating the impact of chronic ethanol on ss/ds RNA sensing and activation of IRF3-mediated cellular responses. Here we propose to extend the scope of this RO1 to address two important aspects of the interaction of alcohol and COVID-19 in people consuming alcohol. In Specific Aim 1, making use of data from the UK Biobank, we will ask whether alcohol consumption or alcohol-related diseases increase risk of infection, hospitalization and mortality. In Specific Aim 2, we will use single cell RNA seq analysis to interrogate the impact of alcohol consumption on anti-viral responses in peripheral innate and adaptive immune cells. Understanding the impact of alcohol use on risk for COVID-19 and characterizing the specific cellular changes in anti-viral responses will meet an important unmet clinical need for guiding public health and medical responses to the COVID-19 pandemic.